14 results on '"Pyrimidines"'
Search Results
2. Baseline genetic abnormalities and effectiveness of osimertinib treatment in patients with chemotherapy-naïve EGFR-mutated NSCLC based on performance status.
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Taniguchi Y, Tamiya A, Osuga M, Harada D, Isa SI, Nakamura K, Mizumori Y, Shinohara T, Yanai H, Nakatomi K, Oki M, Mori M, Kuwako T, Yamazaki K, Tamura A, Ando M, and Koh Y
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- Humans, Male, Female, Aged, Middle Aged, Prospective Studies, Antineoplastic Agents therapeutic use, Japan, Progression-Free Survival, Aged, 80 and over, Adult, beta Catenin genetics, Indoles, Pyrimidines, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung mortality, Acrylamides therapeutic use, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms mortality, ErbB Receptors genetics, Aniline Compounds therapeutic use, Mutation
- Abstract
Background/aim: For patients treated with osimertinib as first-line therapy, there have been no studies comparing both progression-free survival (PFS) and overall survival (OS) according to performance status (PS). Furthermore, no studies have examined differences in baseline genetic abnormalities between patients with poor and good PS. Therefore, we aimed to investigate differences in baseline genetic abnormalities and treatment effects between patients with poor and good PS who received osimertinib as the primary treatment., Patients and Methods: This is a secondary analysis of the ELUCIDATOR study, which is a multi-center prospective observational study in Japan that assessed mechanisms underlying resistance to osimertinib as first-line treatment for advanced non-small cell lung cancer with epidermal growth factor receptor mutations., Results: There were 153 and 25 patients in the good and poor PS groups, respectively. Multivariate analysis revealed no significant between-group differences in PFS (hazards ratio [HR]: 0.98, 95% confidence interval [CI]: 0.52-1.72, p = 0.946). Multivariate analysis of OS revealed that poor PS was a poor prognostic factor (HR: 2.67, 95% CI: 1.43-4.73, p = 0.003). Regarding baseline genetic abnormalities, there was a significant increase in APC-positive cases (20.0% vs. 2.2%, p = 0.009) and a trend toward more CTNNB1-positive cases in the poor PS group than in the good PS group (14.3% vs. 2.9%, p = 0.062)., Conclusion: There was no between-group difference in PFS, although OS was significantly inferior in the poor PS group. Additionally, there was a significant increase in APC-positive cases and a trend toward more CTNNB1-positive cases in the poor PS group., (© 2024. The Author(s).)
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- 2024
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3. Evaluation of prescribing patterns of switching to and add-on lemborexant in patients treated with hypnotic medication: a nationwide claims database study in Japan.
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Tanaka-Mizuno S, Fujimoto K, Mishima K, Sakata Y, Fukasawa T, Mizuno K, Yoshida S, Ishii M, Taninaga T, Kubota N, Moline M, and Kawakami K
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- Humans, Male, Female, Retrospective Studies, Middle Aged, Aged, Japan, Adult, Cohort Studies, Drug Therapy, Combination, Drug Substitution statistics & numerical data, Pyridines therapeutic use, Pyridines administration & dosage, Pyridines adverse effects, Young Adult, Pyrimidines, Hypnotics and Sedatives therapeutic use, Hypnotics and Sedatives administration & dosage, Hypnotics and Sedatives adverse effects, Sleep Initiation and Maintenance Disorders drug therapy, Databases, Factual, Practice Patterns, Physicians' statistics & numerical data
- Abstract
Background: When considering changing hypnotic pharmacotherapy, lemborexant has attracted attention as a candidate due to its effectiveness and safety profile. However, few studies have investigated switching patterns in clinical practice., Research Design and Methods: We conducted a retrospective cohort study using a nationwide claims database. Patients prescribed a single hypnotic who either subsequently switched to (switching cohort) or were additionally prescribed (add-on cohort) lemborexant between July 2020 and December 2021 were identified. Proportion of successful switching was defined as remaining on lemborexant alone or without any hypnotic at 6 months after lemborexant initiation., Results: The success proportion was 70.1% in the switching cohort ( n = 4,861) and 38.6% in the add-on cohort ( n = 9,423). In the add-on cohort, the success proportion was lower in patients with a hypnotic history of ≥180 days (31.4%) and in patients whose prescribed hypnotic was a benzodiazepine or non-benzodiazepine (31.5% and 37.6%, respectively)., Conclusion: The proportion of successful switching was higher in patients who switched to lemborexant than in those who added lemborexant as a concomitant treatment. The lower success proportion in the add-on cohort might be related to clinically more severe insomnia, and/or a concomitant prescription of benzodiazepine or non-benzodiazepine, from which discontinuation may be challenging.
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- 2024
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4. Safety and Efficacy of Lemborexant in Insomnia Patients: Results of a Postmarketing Observational Study of Dayvigo ® Tablets.
- Author
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Mishima K, Fujimoto K, Endo A, and Ishii M
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- Humans, Male, Female, Middle Aged, Adult, Prospective Studies, Aged, Treatment Outcome, Young Adult, Pyridines adverse effects, Pyridines therapeutic use, Pyridines administration & dosage, Japan, Aged, 80 and over, Pyrimidines, Sleep Initiation and Maintenance Disorders drug therapy, Product Surveillance, Postmarketing, Tablets
- Abstract
Background and Objective: A prospective, postmarketing observational study was conducted to evaluate the safety and efficacy of lemborexant (LEM) tablets in daily clinical practice in Japan. No other studies of a similar size have been conducted since the marketing approval of LEM, making this the first report of its kind., Methods: Insomnia patients (n = 550) administered LEM (5-10 mg daily) for the first time were enrolled. Adverse events were collected for target events (somnolence, parasomnia, narcolepsy and associated conditions, suicidal ideation and suicidal behavior). Overall improvement of insomnia symptoms was assessed by the investigator based on the patient's complaint. Subjective sleep onset latency (sSOL) and subjective total sleep time (sTST) were investigated as sleep parameters., Results: A case report form was obtained from 539 patients. The incidence of adverse drug reactions (ADRs) was 7.65% for somnolence, 1.76% for nightmares, 0.59% for abnormal dreams, and 0.20% for sleep paralysis. No serious ADRs or ADRs related to suicidal ideation or suicidal behavior were observed. The efficacy rate at the final evaluation was 80.83%. Decreased sSOL and increased sTST were observed as assessed starting from Week 8 of treatment., Conclusion: Based on the results of this study, the safety result was consistent with the safety profile described in the current package insert. Efficacy results also indicated that LEM is clinically useful., (© 2024. The Author(s).)
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- 2024
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5. Real-World Data on Subsequent Therapy for First-Line Osimertinib-Induced Pneumonitis: Safety of EGFR-TKI Rechallenge (Osi-risk Study TORG-TG2101).
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Nishioka N, Imai H, Endo M, Notsu A, Doshita K, Igawa S, Yokouchi H, Ninomiya T, Tokito T, Soda S, Fujiwara T, Asao T, Nakamichi S, Kawamura T, Inomata M, Nakashima K, Ito K, Goto Y, Umeda Y, Hirai S, Ushio R, Yokoo K, Takeda T, Fukui T, Ishihara M, Osaki T, Kubo S, Fujiwara T, Yamamoto C, Tsuda T, Tamura N, Hosokawa S, Chihara Y, Ikeda S, Furuya N, Nakahara Y, Miura S, and Okamoto H
- Subjects
- Humans, Male, Female, Aged, Retrospective Studies, Middle Aged, Aged, 80 and over, Japan, Indoles, Pyrimidines, Acrylamides therapeutic use, Acrylamides pharmacology, Aniline Compounds therapeutic use, Aniline Compounds pharmacology, Aniline Compounds adverse effects, Pneumonia chemically induced, Lung Neoplasms drug therapy, ErbB Receptors, Protein Kinase Inhibitors adverse effects, Protein Kinase Inhibitors therapeutic use, Protein Kinase Inhibitors pharmacology
- Abstract
Background: Although osimertinib is a promising therapeutic agent for advanced epidermal growth factor receptor (EGFR) mutation-positive lung cancer, the incidence of pneumonitis is particularly high among Japanese patients receiving the drug. Furthermore, the safety and efficacy of subsequent anticancer treatments, including EGFR-tyrosine kinase inhibitor (TKI) rechallenge, which are to be administered after pneumonitis recovery, remain unclear., Objective: This study investigated the safety of EGFR-TKI rechallenge in patients who experienced first-line osimertinib-induced pneumonitis, with a primary focus on recurrent pneumonitis., Patients and Methods: We retrospectively reviewed the data of patients with EGFR mutation-positive lung cancer who developed initial pneumonitis following first-line osimertinib treatment across 34 institutions in Japan between August 2018 and September 2020., Results: Among the 124 patients included, 68 (54.8%) patients underwent EGFR-TKI rechallenge. The recurrence rate of pneumonitis following EGFR-TKI rechallenge was 27% (95% confidence interval [CI] 17-39) at 12 months. The cumulative incidence of recurrent pneumonitis was significantly higher in the osimertinib group than in the first- and second-generation EGFR-TKI (conventional EGFR-TKI) groups (hazard ratio [HR] 3.1; 95% CI 1.3-7.5; p = 0.013). Multivariate analysis revealed a significant association between EGFR-TKI type (osimertinib or conventional EGFR-TKI) and pneumonitis recurrence, regardless of severity or status of initial pneumonitis (HR 3.29; 95% CI 1.12-9.68; p = 0.03)., Conclusions: Osimertinib rechallenge after initial pneumonitis was associated with significantly higher recurrence rates than conventional EGFR-TKI rechallenge., (© 2024. The Author(s).)
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- 2024
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6. Efficacy and Safety of Transitioning to Lemborexant from Z-drug, Suvorexant, and Ramelteon in Japanese Insomnia Patients: An Open-label, Multicenter Study.
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Ozone M, Hirota S, Ariyoshi Y, Hayashida K, Ikegami A, Habukawa M, Ohshima H, Harada D, Hiejima H, Kotorii N, Murotani K, Taninaga T, and Uchimura N
- Subjects
- Humans, Japan, Prospective Studies, Sleep Initiation and Maintenance Disorders drug therapy, Triazoles, Azepines, Pyridines, Indenes, Pyrimidines
- Abstract
Introduction: For patients with chronic insomnia, conventional therapy may not always provide satisfactory efficacy and safety. Thus, switching to an alternative therapeutic agent can be explored. However, there is a lack of prospective studies evaluating the effectiveness of such changes. This prospective, non-randomized, open-label, interventional, multicenter study assessed whether Japanese patients with chronic insomnia dissatisfied with treatment could transition directly to lemborexant (LEM) from four cohorts-non-benzodiazepine sedative-hypnotic (zolpidem, zopiclone, or eszopiclone) monotherapy, dual orexin receptor antagonist (suvorexant) monotherapy, suvorexant + benzodiazepine receptor agonists (BZRAs), and melatonin receptor agonist (ramelteon) combination. We evaluated whether transitioning to LEM improved patient satisfaction based on efficacy and safety., Methods: The primary endpoint was the proportion of successful transitions to LEM at 2 weeks (titration phase end), defined as the proportion of patients on LEM by the end of the 2-week titration phase who were willing to continue on LEM during the maintenance phase (Weeks 2-14). Patient satisfaction and safety (the incidence of treatment-emergent adverse events [TEAEs]) were assessed at 14 weeks (end of titration and maintenance phases)., Results: Among the 90 patients enrolled, 95.6% (95% confidence interval: 89.0-98.8%) successfully transitioned to LEM at 2 weeks. The proportions of patients who successfully continued on LEM were 97.8% and 82.2% at the end of the titration and maintenance phases (Weeks 2 and 14), respectively. The overall incidence of TEAEs was 47.8%; no serious TEAEs occurred. In all cohorts, the proportions of patients with positive responses were higher than the proportions with negative responses on the three scales of the Patient Global Impression-Insomnia version. During the maintenance phase, Insomnia Severity Index scores generally improved at Weeks 2, 6, and 14 of LEM transition., Conclusions: Direct transition to LEM may be a valid treatment option for patients with insomnia who are dissatisfied with current treatment., Trial Registration: ClinicalTrials.gov identifier, NCT04742699., (© 2024. The Author(s).)
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- 2024
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7. Long-term experience with tepotinib in Japanese patients with MET exon 14 skipping NSCLC from the Phase II VISION study.
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Morise M, Kato T, Matsumoto S, Inoue T, Sakamoto T, Tokito T, Atagi S, Kozuki T, Takeoka H, Chikamori K, Shinagawa N, Tanaka H, Horii E, Adrian S, Bruns R, Johne A, Paik PK, and Sakai H
- Subjects
- Humans, Male, Middle Aged, Aged, Aged, 80 and over, Female, Japan, Exons genetics, Protein Kinase Inhibitors adverse effects, Mutation, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Piperidines, Pyridazines, Pyrimidines
- Abstract
Tepotinib is a highly selective MET tyrosine kinase inhibitor (TKI) that has demonstrated robust and durable clinical activity in patients with MET exon 14 (METex14) skipping non-small-cell lung cancer (NSCLC). In the Phase II VISION study, patients received oral tepotinib 500 mg once daily. The primary endpoint was an objective response by an independent review committee (IRC) according to RECIST v1.1 criteria. The secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Here we report the analysis of the efficacy and safety of tepotinib in all Japanese patients with advanced METex14 skipping NSCLC from VISION (n = 38) with >18 months' follow-up. The median age of the Japanese patients was 73 years (range 63-88), 39.5% of patients were ≥75 years old, 68.4% were male, 55.3% had a history of smoking, 76.3% had adenocarcinoma, and 10.5% of patients had known brain metastases at baseline. Overall, the objective response rate (ORR) was 60.5% (95% confidence interval (CI): 43.4, 76.0) with a median DOR of 18.5 months (95% CI: 8.3, not estimable). ORR in treatment-naïve patients (n = 18) was 77.8% (95% CI: 52.4, 93.6), and in patients aged ≥75 years (n = 15), ORR was 73.3% (95% CI: 44.9, 92.2). The most common treatment-related adverse event (AE) with any grade was blood creatinine increase (65.8%), which resolved following tepotinib discontinuation. Other common treatment-related AEs were peripheral edema (60.5%), hypoalbuminemia (34.2%), diarrhea (28.9%), and nausea (15.8%). In summary, tepotinib demonstrated robust and durable clinical activity irrespective of age or therapy line, with a manageable safety profile in Japanese patients with METex14 skipping NSCLC enrolled in VISION., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
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- 2024
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8. Comparison of efficacy between clazosentan and fasudil hydrochloride-based management of vasospasm after subarachnoid hemorrhage focusing on older and WFNS grade V patients: a single-center experience in Japan.
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Mochizuki T, Ryu B, Shima S, Kamijyo E, Ito K, Ando T, Kushi K, Sato S, Inoue T, Kawashima A, Kawamata T, Okada Y, and Niimi Y
- Subjects
- Aged, Humans, Cerebral Infarction, Dioxanes, Japan, Pyridines, Pyrimidines, Retrospective Studies, Sulfonamides, Tetrazoles, Treatment Outcome, 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine analogs & derivatives, Subarachnoid Hemorrhage surgery, Vasospasm, Intracranial drug therapy
- Abstract
Subarachnoid hemorrhage often leads to poor outcomes owing to vasospasm, even after successful aneurysm treatment. Clazosentan, an endothelin receptor inhibitor, has been proven to be an effective treatment for vasospasms in a Japanese randomized controlled trial. However, its efficacy in older patients (≥ 75 years old) and those with World Federation of Neurosurgical Societies (WFNS) grade V has not been demonstrated. We retrospectively evaluated the efficacy of clazosentan in older patients and those with WFNS grade V, using real-world data. Patients with subarachnoid hemorrhage treated before and after the introduction of clazosentan were retrospectively evaluated. The patients were categorized into two groups (clazosentan era versus pre-clazosentan era), in which vasospasm management and outcomes were compared. Vasospasms were managed with fasudil hydrochloride-based (pre-clazosentan era) or clazosentan-based treatment (clazosentan era). Seventy-eight patients were included in this study: the clazosentan era (n = 32) and pre-clazosentan era (n = 46). Overall, clazosentan significantly reduced clinical vasospasms (clazosentan era: 31.3% versus pre-clazosentan era: 60.9%, p = 0.01), delayed cerebral ischemia (DCI) (9.4% versus 39.1%, p = 0.004), and vasospasm-related morbidity and mortality (M/M) (3.1% versus 19.6%, p = 0.03). In subgroup analysis of older patients or those with WFNS grade V, no significant difference was observed in clinical outcomes, although both DCI and vasospasm-related M/M were lower in the clazosentan era. Clazosentan was more effective than fasudil-based management in preventing DCI and reducing vasospasm-related M/M. Clazosentan could be used safely in older patients and those with WFNS grade V, although clinical outcomes in these patients were comparable to those of conventional treatment., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2024
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9. Six-month safety and effectiveness of tofacitinib in patients with rheumatoid arthritis in Japan: Interim analysis of post-marketing surveillance.
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Kuwana M, Sugiyama N, Momohara S, Atsumi T, Takei S, Tamura N, Harigai M, Fujii T, Matsuno H, Takeuchi T, Yamamoto K, Takasaki Y, Tanigawa M, Endo Y, Hirose T, Morishima Y, Yoshii N, Mimori T, and Takagi M
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- Humans, Male, Japan, Pyrroles adverse effects, Product Surveillance, Postmarketing, Treatment Outcome, Arthritis, Rheumatoid drug therapy, Arthritis, Rheumatoid epidemiology, Antirheumatic Agents adverse effects, Piperidines, Pyrimidines
- Abstract
Objectives: We evaluated the real-world safety/effectiveness of tofacitinib, an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), in patients with RA in Japan registered in a post-marketing surveillance study., Methods: This interim analysis included data from July 2013 to December 2018. Adverse events (AEs), serious AEs (SAEs), Simplified Disease Activity Index (SDAI)/Clinical Disease Activity Index (CDAI)/Disease Activity Score in 28 joints, erythrocyte sedimentation rate [DAS28-4(ESR)] scores, and rates of SDAI/CDAI/DAS28-4(ESR)-defined remission and low disease activity were analysed using 6 months of data. Risk factors for serious infections were assessed by multivariable analyses., Results: Safety and disease activity were evaluated in 6866 and 6649 patients, respectively. Overall, 32.73%/7.37% of patients reported AEs/SAEs. Clinically important AEs with tofacitinib included serious infections/infestations [3.13% of patients; incidence rate (IR; patients with events) 6.91/100 patient-years (PY)], herpes zoster (3.63%; IR 8.02/100 PY), and malignancies (0.68%; IR 1.45/100 PY). SDAI/CDAI/DAS28-4(ESR) scores and remission/low disease activity rates improved over 6 months. Male sex, older age, Steinbrocker's stage IV, history of infection, and diabetes mellitus at baseline were independent risk factors for serious infection., Conclusions: In patients with RA receiving tofacitinib in Japan, safety was consistent with the reported profile, and disease activity improved over 6 months., Study Identifier: NCT01932372., (© Japan College of Rheumatology 2023. Published by Oxford University Press.)
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- 2024
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10. Factors Influencing Discontinuation of Clazosentan Therapy in Elderly Patients with Aneurysmal Subarachnoid Hemorrhage: A Retrospective Study from a Japanese Single Center.
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Mutoh T, Aono H, Seto W, Kimoto T, Tochinai R, Moroi J, and Ishikawa T
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- Aged, Humans, Retrospective Studies, Japan, Tetrazoles therapeutic use, Hypoxia complications, Subarachnoid Hemorrhage drug therapy, Subarachnoid Hemorrhage complications, Vasospasm, Intracranial etiology, Dioxanes, Pyridines, Pyrimidines, Sulfonamides
- Abstract
BACKGROUND Clazosentan is an endothelin receptor antagonist approved in Japan for preventing cerebral vasospasm and vasospasm-associated cerebral ischemia and infarction. This study included elderly patients aged ≥75 years with aneurysmal subarachnoid hemorrhage (SAH) and aimed to evaluate the factors associated with discontinuing anti-vasospasm therapy with clazosentan. MATERIAL AND METHODS In this single-center retrospective observational study, we extracted diagnostic and therapeutic work-up data of consecutive 40 patients with SAH treated with clazosentan infusion (10 mg/h) as first-line anti-vasospasm therapy between May 2022 and August 2023. Patient data were compared between the discontinued and completed groups, and related factors for the discontinuation were further analyzed. RESULTS Clazosentan was discontinued in 22% (n=9) of patients due to intolerable dyspnea accompanied by hypoxemia at 5±3 days after therapy initiation, in which 44% (n=4) were elderly (≥75 years). Patients who discontinued clazosentan therapy showed significantly lower urine volumes compared with those who completed the therapy (P<0.05). Multivariate regression analysis revealed that day-to-day urine volume variance and older age were independent risk factors for drug cessation (P<0.05). The cut-off value for predicting clazosentan discontinuation was -0.7 mL/kg/h with sensitivity of 86% and specificity of 75% (area under the curve: 0.76±0.10; 95% confidence interval: 0.56-0.96; P=0.035). CONCLUSIONS Our results suggest that approximately 20% of SAH patients suffered from intolerable respiratory symptoms attributable to hypoxemia. We found that both reduced day-to-day urine volume variation and older age are independent risk factors for drug discontinuation.
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- 2024
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11. Long-term treatment with fostamatinib in Japanese patients with primary immune thrombocytopenia: An open-label extension study following a phase 3 placebo-controlled, double-blind, parallel-group study.
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Kuwana M, Ito T, Kowata S, Hatta Y, Fujimaki K, Naito K, Kurahashi S, Kagoo T, Tanimoto K, Saotome S, and Tomiyama Y
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- Humans, Japan, Pyridines adverse effects, Oxazines adverse effects, Double-Blind Method, Treatment Outcome, Purpura, Thrombocytopenic, Idiopathic drug therapy, Purpura, Thrombocytopenic, Idiopathic chemically induced, Aminopyridines, Morpholines, Pyrimidines
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- 2024
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12. Cardiopulmonary Events of the Elderly (≥75 Years) during Clazosentan Therapy after Subarachnoid Hemorrhage: A Retrospective Study from a Tertiary Stroke Center in Japan.
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Mutoh T, Aono H, Seto W, Kimoto T, Tochinai R, Moroi J, and Ishikawa T
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- Aged, Female, Humans, Aged, 80 and over, Retrospective Studies, Japan epidemiology, Weight Gain, Subarachnoid Hemorrhage complications, Subarachnoid Hemorrhage drug therapy, Vasospasm, Intracranial, Stroke complications, Pyrimidines, Pyridines, Dioxanes, Sulfonamides, Tetrazoles
- Abstract
Clazosentan has been shown to prevent vasospasm and reduce mortality in patients after aneurysmal subarachnoid hemorrhage (SAH) and has been approved for clinical use in Japan; however, its systemic events in the elderly (aged ≥ 75 years) have not been well-documented. Here, we report serious/intolerable cardiopulmonary complications requiring discontinuation of drug therapy in elderly SAH patients. In this single-center case series study, medical records of consecutive SAH patients treated postoperatively with clazosentan (10 mg/h) between June 2022 and May 2023 were reviewed retrospectively. Thirty-three patients received clazosentan therapy, of whom six were elderly with a mean age of 80.3 ± 5.2 (range 75-89) years. Among them, despite no obvious medical history of systemic abnormalities, clazosentan was discontinued in three (50%) patients due to pleural effusion and hypoxemia with or without hypotension at 5 ± 3 days after therapy initiation, which was higher than the incidence for younger patients (15%). The elderly patients had significantly lower urine output (1935 ± 265 vs. 1123 ± 371 mL/day, p = 0.03) and greater weight gain (2.1 ± 1.1 vs. 4.2 ± 1.9 kg from baseline, p = 0.04) than patients who completed the therapy. One 89-year-old female developed congestive heart failure and hydrostatic pulmonary edema associated with increased intravascular and lung volumes even after therapy was discontinued, while the remaining two cases recovered within 2 days after drug cessation. These results suggest that elderly patients are more vulnerable to fluid retention and have a higher risk of cardiopulmonary complications during clazosentan therapy than younger patients. Careful monitoring of urine volume and weight gain and caution regarding age- and therapy-related hemodynamic insufficiencies are required.
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- 2024
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13. A phase 3, randomized, double-blind, clinical study to evaluate the long-term safety and efficacy of gefapixant in Japanese adult participants with refractory or unexplained chronic cough.
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Niimi A, Sagara H, Kikuchi M, Arano I, Sato A, Shirakawa M, La Rosa C, and Muccino D
- Subjects
- Adult, Chronic Disease, Cough drug therapy, Double-Blind Method, Female, Humans, Japan epidemiology, Male, Middle Aged, Pyrimidines, Quality of Life, Sulfonamides, Carcinoma, Renal Cell, Kidney Neoplasms
- Abstract
Background: In two phase 3, global clinical trials (COUGH-1 and COUGH-2), the P2X3-receptor antagonist gefapixant significantly reduced objective 24-h cough frequency in participants with refractory or unexplained chronic cough (RCC or UCC) at a dosage of 45 mg twice daily (BID), with an acceptable safety profile. The primary objective of this phase 3, randomized, double-blind, parallel-group study was to assess the safety and tolerability of gefapixant in Japanese participants with RCC or UCC (ClinicalTrials.gov, NCT03696108; JAPIC-CTI, 184154)., Methods: Participants aged ≥20 years with chronic cough lasting ≥4 months and a diagnosis of RCC or UCC despite treatment in accordance with Japanese Respiratory Society guidelines were randomized 1:1 to receive gefapixant 15 or 45 mg BID for 52 weeks. The primary objective was to evaluate the safety and tolerability of gefapixant, including adverse events (AEs) and discontinuations due to AEs. Cough-specific quality of life was assessed using the Leicester Cough Questionnaire as a secondary objective., Results: Of 169 randomized and treated participants, 63% were female and mean age was 58 years. Adverse events were reported by 79 (94%) and 82 (96%) participants in the 15- and 45-mg BID groups, respectively. Most treatment-related AEs were taste related. Discontinuations due to AEs occurred in 6 (7%) and 17 (20%) participants receiving gefapixant 15 or 45 mg BID, respectively. There were no serious treatment-related AEs or deaths. Leicester Cough Questionnaire total scores improved from baseline through Week 52., Conclusions: Gefapixant had an acceptable safety profile, with no serious treatment-related AEs in Japanese participants., (Copyright © 2022 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)
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- 2022
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14. FLUID study: study protocol for an open-label, single-centre pilot study to investigate the efFect of Lemborexant on sleep management in Japanese sUbjects aged 50 years and older with Insomnia Disorder.
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Okada I, Iwamoto K, Miyata S, Fujimoto A, Tanaka M, Amano M, Matsuyama N, Taoka T, Naganawa S, and Ozaki N
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- Aged, Amyloid beta-Peptides, Double-Blind Method, Humans, Japan, Middle Aged, Pilot Projects, Pyridines, Pyrimidines, Sleep, Sleep Quality, Sleep Initiation and Maintenance Disorders drug therapy
- Abstract
Introduction: Bidirectional associations have been reported between sleep disturbance and both cognitive impairment, including Alzheimer's disease and amyloid beta-peptide (Aβ) accumulation. These relationships can be explained by the glymphatic system, which acts as a garbage drainage system in the brain. As interstitial fluid dynamics are suggested to increase during sleep, clearance of Aβ can be influenced by sleep disturbance or deprivation. We hypothesised that using lemborexant, an orexin receptor antagonist, to improve sleep quality would also improve the function of the glymphatic system. We plan to examine the effect of lemborexant on sleep quality and the glymphatic system among patients with insomnia disorder., Methods and Analysis: This pilot study is designed as an open-label, single-arm, single-centre trial. Thirty patients aged 50 years and over with insomnia will be recruited. The participants will take lemborexant (5 mg) at bedtime for 12 weeks and undergo a home-based sleep study at baseline and weeks 4 and 12, as well as MRI examinations to evaluate the glymphatic system at baseline and week 12. The primary outcome will be changes in objective sleep parameters as evaluated using a sleep monitoring system. The secondary outcomes will be changes in subjective sleep parameters. The relationships between changes in sleep parameters and the glymphatic system will be evaluated using diffusion tensor image analysis along the perivascular space, which is called the ALPS-index. Sleep parameters and the ALPS-index will be analysed using a paired t-test or Pearson's correlation coefficient., Ethics and Dissemination: The study protocol was approved by Nagoya University Certified Review Board. The findings from this research will be published in peer-reviewed journals and be presented at local, national and international conferences., Trial Registration Number: jRCTs041210024., Competing Interests: Competing interests: IO, SM, MA and NM have no conflicts of interest to declare. KI has received speakers’ honoraria from Eisai, Kyowa, Meiji Seika Pharma, Otsuka, Sumitomo Dainippon, Taisho, Takeda and Towa. AF and MT are employees of Eisai, Japan. TT has received research funding from Canon Medical Systems Corporation. SN has received speakers’ honoraria from Eisai, Siemens Healthcare Japan, Guerbet, GE Healthcare Pharma, Nihon Medi-Physics, FUJIFILM Toyama Chemical, Bayer and Canon Medical Systems Corporation. NO has received research support or speakers’ honoraria from, or has served as a consultant to, Sumitomo Dainippon, Eisai, Otsuka, KAITEKI, Mitsubishi Tanabe, Shionogi, Eli Lilly, Mochida, DAIICHI SANKYO, Nihon Medi-Physics, Takeda, Meiji Seika Pharma, EA Pharma, Pfizer, MSD, Lundbeck Japan, Taisho Pharma, Janssen, UCB and Shionogi, Nihon Medi-Physics, Tsumura, Novartis and Astellas. Eisai funded this study and participated in the planning of this study. Eisai will also review findings, commission the study report, and review the papers before they are submitted for publication., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2021
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